We will investigate whether the superior dose distributions (as compared to x-rays) of protons provides a therapeutic gain in the treatment of particular tumors. The sharp distal fall-off and lateral penumbra of proton dose distributions, and our ability to shape the distal edge (and also the proximal edge, during the course of the proposed research), of the proton stopping region, allow proton treatment volumes to conform more closely to the target volume than is possible with x-rays. As a consequence, the dose to the target can be increased and hence also the tumor control probability. Also, because there will be less normal tissue outside the target volume irradiated to a high dose, we anticipate that the frequency and severity of normal tissue damage will be reduced. In Project 1 we will design and carry out Phase I/II and III clinical trials in disease sites where we expect a significant clinical gain as a result of improved dose distributions achieved with protons. In Project 2 we will use the patient database acquired in Project 1 to analyze the dose response relationships for normal tissues and tumors. We will also conduct comparative treatment planning studies to inform us of possible new treatment sites and techniques. Project 3 provides the beam delivery, treatment planning, and treatment systems for the clinical studies conducted in Project 1. During the course of this program we will transfer the clinical research from the Harvard Cyclotron Laboratory to the Northeast Proton Therapy Center (NPTC). The new center, opening in mid- 1998, will have three treatment rooms, 2 with isocentric gantries, higher energy proton beams (up to 235 MeV), and state-of -the -art control systems for treatment, safety and accelerator control/ diagnostics. The NPTC will make it possible for us to provide proton treatments which are technically equivalent to advanced x-ray conformal therapy and therefore we can-test the theoretical superiority of proton dose distributions against the best x-ray treatments. Our very positive clinical results in skull base tumors and uveal melanomas, made possible by higher tumor doses without significant increases in treatment morbidity, give us confidence that we will have successes in other disease sites where tumor doses are now limited by sensitive normal structures. In addition, we have developed referral systems and clinical affiliate relationships which ensure that we will have adequate patients to conduct clinical trials in reasonable time frames. Most importantly, our team of experienced and dedicated researchers (physicians, clinical physicists, biostatisticians, and accelerator physicists) and excellent support staff, provide a breadth and depth of resources which will enable us to carry out the proposed research.